CN101815483B - Prosthetic material for living organ - Google Patents

Prosthetic material for living organ Download PDF

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Publication number
CN101815483B
CN101815483B CN2008801026656A CN200880102665A CN101815483B CN 101815483 B CN101815483 B CN 101815483B CN 2008801026656 A CN2008801026656 A CN 2008801026656A CN 200880102665 A CN200880102665 A CN 200880102665A CN 101815483 B CN101815483 B CN 101815483B
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lactide
living organ
type
prosthetic material
porous layer
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CN101815483A (en
Inventor
坂元悠纪
松田晶二郎
新冈俊治
市原有起
筏义人
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Gunze Ltd
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Gunze Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/249921—Web or sheet containing structurally defined element or component
    • Y10T428/249953—Composite having voids in a component [e.g., porous, cellular, etc.]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T442/00—Fabric [woven, knitted, or nonwoven textile or cloth, etc.]
    • Y10T442/60—Nonwoven fabric [i.e., nonwoven strand or fiber material]

Abstract

The object is to provide a prosthetic material for a living organ, which can withstand the venous pressure satisfactorily, can prevent the leakage of blood or the rupture of blood vessels, can serve as a scaffold for the regeneration of a blood vascular tissue, and does not need further surgery or the like. Thus, disclosed is a prosthetic material for a living organ, which comprises a laminate composed of a film layer comprising a bioresorbable material and a porous layer comprising a bioresorbable material.

Description

Prosthetic material for living organ
Technical field
The present invention relates to be enough to bear arterial pressure and prevent spilling or the prosthetic material for living organ that breaks, becomes the regenerated support of vascular tissue and do not need to perform the operation once more etc. of blood vessel of blood.
Background technology
Hypoplastic left heart syndrome is from left ventricle to aortic valve, the incomplete disease of aortal vascularization, is the disease of the highest, the treatment difficulty of mortality rate in present children's's cardiovascular surgery.In addition, the aortic arch stenosis, be that the narrow or aortal part of aortal intermediate extreme takes place from disconnected disease from disconnected disease.The cardiopathic characteristic of these baby's congenitals is aortal blood vessel self and takes place damaged.Therefore; What carry out at present is following art formula: use to sacrifice and (for example compare other lower tremulous pulse of importance with aorta; Left subclavian artery etc.), on blood vessel, cut otch and method (the lappet plasty that distends the blood vessels; Flap method), perhaps remedy the absolute deficiency of vascular bed area with repair materials.
As this repair materials, for example, use from the body-centered peplos.Peplos has with the affinity of blood vessel high nor the characteristic of problem such as can repel from the body-centered.But peplos considers in nature that from it the amount that can use is limited from the body-centered.In fact, the problem that can only in operation first, use of existence.Therefore, the prosthetic material for living organ that is made up of artificial material is studied.
As the prosthetic material for living organ that constitutes by artificial material; For example, put down in writing the cyclic blood vessel repair materials that the biological non-absorbent intermediate layer by biological non-absorbent porous skin of polyester fiber etc. and internal layer and silicone rubber etc. constitutes in the patent documentation 1.In addition, put down in writing the porous internal layer that will constitute by silicone rubber etc. in the patent documentation 2 and the outer laminated that constitutes by polyester fiber etc. and the blood vessel repair materials that obtains.In addition, also carried out utilizing the trial of the so-called artificial blood vessel that constitutes by polyethylene or fluororesin etc. as prosthetic material for living organ.
But; Particularly will by these not the prosthetic material for living organ that constitutes of absorbent material be used under children's's the situation; Have following big problem: the blood vessel of mending the part that prosthetic material for living organ is arranged can not the growth fully with children's's growth, or that the probability of healing or calcification takes place is very high, thereby need be that operation is implemented in displacement again once more.
Patent documentation 1: international monopoly discloses pamphlet No. 99/12496
Patent documentation 2: japanese kokai publication hei 11-99163 communique
Summary of the invention
In view of above-mentioned present situation, the object of the present invention is to provide can be enough to bear arterial pressure and prevent spilling or the regenerated support of the vascular tissue of breaking, become blood of blood vessel and the prosthetic material for living organ that do not need to perform the operation once more etc. of blood.
The present invention relates to a kind of prosthetic material for living organ, be made up of the layered product of thin layer and porous layer, said thin layer is made up of biological absorptive material, and said porous layer is made up of biological absorptive material.
Below, the present invention is elaborated.
The inventor furthers investigate; The result finds: by the layered product of biological absorptive material thin layer that constitutes and the porous layer that is made up of biological absorptive material; Even under situation about using as prosthetic material for living organ, also can be enough to bear arterial pressure and prevent spilling of blood or breaking of blood vessel, become the support of revascularization simultaneously and the blood vessel that makes the patient is regenerated in during extremely short; And; The back is decomposed, is absorbed and can calcification during certain, need not change through operation once more, thereby accomplish the present invention.
Prosthetic material for living organ of the present invention is made up of the layered product of thin layer and porous layer.
Said thin layer is given the intensity that prosthetic material for living organ of the present invention is enough to bear arterial pressure, thus the effect of the anti-leak-stopping blood of performance.In addition, said thin layer is also brought into play and is prevented that air from spilling, preventing that the cell of sowing is interior along a certain direction entering effects such as (healing prevent effect) during spilling, prevent to be organized in necessarily.
Said porous layer is made up of non-woven fabrics, sponge or their complex, perhaps makes cell invade the effect as the support of revascularization of bringing into play by blood vessel on every side through the sowing cell.
Constitute the not special restriction of biological absorptive material of said thin layer, for example can enumerate: gather Acetic acid, hydroxy-, bimol. cyclic ester, polylactide (D, L, DL type), polycaprolactone, Acetic acid, hydroxy-, bimol. cyclic ester-lactide (D, L, DL type) copolymer, Acetic acid, hydroxy-, bimol. cyclic ester-epsilon-caprolactone copolymer, lactide (D, L, DL type)-epsilon-caprolactone copolymer, gather dioxanone, Acetic acid, hydroxy-, bimol. cyclic ester-lactide (D, L, DL type)-synthetic absorbability macromolecules such as epsilon-caprolactone copolymer; And natural polymers such as gelatin, collagen or fibrin.These biological absorptive materials can use separately, also can two or more and usefulness.Wherein, Consider from high strength, flexibility and these aspects of decomposition behavior of showing appropriateness, preferred: as to be selected from least a by in lactide (D, L, DL type)-epsilon-caprolactone copolymer, Acetic acid, hydroxy-, bimol. cyclic ester-epsilon-caprolactone copolymer and the Acetic acid, hydroxy-, bimol. cyclic ester-lactide group that (D, L, DL type)-epsilon-caprolactone copolymer is formed.
Under the situation of said thin layer by formations such as lactide (D, L, DL type)-epsilon-caprolactone copolymers, the preferred lower limit of the content of lactide is 40 moles of % in lactide (D, L, DL type)-epsilon-caprolactone copolymer, and preferred upper limit is 80 moles of %.If the content of lactide is lower than 40 moles of %, then can not obtain to bear the required intensity of arterial pressure sometimes.If surpass 80 moles of %, it is insufficient sometimes then to be close to the required flexibility of blood vessel.Be limited to 50 moles of % under lactide content preferred, be limited to 75 moles of % on preferred.
Under the situation of said thin layer by formations such as lactide (D, L, DL type)-epsilon-caprolactone copolymers, the preferred lower limit of the weight average molecular weight of lactide (D, L, DL type)-epsilon-caprolactone copolymer is 100000, and preferred upper limit is 500000.If the weight average molecular weight of said lactide (D, L, DL type)-epsilon-caprolactone copolymer is lower than 100000, then can not obtain to bear the required intensity of arterial pressure sometimes.If surpass 500000, then the dissolubility in solvent reduces or the processability reduction sometimes.Be limited to 150000 under the weight average molecular weight of said lactide (D, L, DL type)-epsilon-caprolactone copolymer preferred, be limited to 400000 on preferred.
The not special restriction of the thickness of said thin layer preferably is limited to 30 μ m down, is limited to 1mm on preferably.Deform if the thickness of said thin layer less than 30 μ m, then is not enough to bear arterial pressure sometimes or break.If surpass 1mm, then can not fully be close to blood vessel sometimes and fix.Be limited to 50 μ m under the thickness of said thin layer preferred, be limited to 800 μ m on preferred.
Constitute the not special restriction of biological absorptive material of said porous layer, for example can enumerate: gather Acetic acid, hydroxy-, bimol. cyclic ester, polylactide (D, L, DL type), Acetic acid, hydroxy-, bimol. cyclic ester-lactide (D, L, DL type) copolymer, Acetic acid, hydroxy-, bimol. cyclic ester-epsilon-caprolactone copolymer, lactide (D, L, DL type)-epsilon-caprolactone copolymer, gather dioxanone, Acetic acid, hydroxy-, bimol. cyclic ester-lactide (D, L, DL type)-synthetic absorbability macromolecules such as epsilon-caprolactone copolymer.These biological absorptive materials can use separately, also can two or more and usefulness.Wherein, Consider from high strength, flexibility and these aspects of decomposition behavior of showing appropriateness, preferred: as to be selected from least a by in lactide (D, L, DL type)-epsilon-caprolactone copolymer, Acetic acid, hydroxy-, bimol. cyclic ester-epsilon-caprolactone copolymer and the Acetic acid, hydroxy-, bimol. cyclic ester-lactide group that (D, L, DL type)-epsilon-caprolactone copolymer is formed.
Under the situation of said porous layer by formations such as lactide (D, L, DL type)-epsilon-caprolactone copolymers, the preferred lower limit of the content of lactide is 40 moles of % in lactide (D, L, DL type)-epsilon-caprolactone copolymer, and preferred upper limit is 80 moles of %.If the content of lactide is lower than 40 moles of %, then intensity is insufficient sometimes.If surpass 80 moles of %, it is insufficient sometimes then to be close to the required flexibility of blood vessel.Be limited to 50 moles of % under lactide content preferred, be limited to 75 moles of % on preferred.
Under the situation of said porous layer by formations such as lactide (D, L, DL type)-epsilon-caprolactone copolymers, the preferred lower limit of the weight average molecular weight of lactide (D, L, DL type)-epsilon-caprolactone copolymer etc. is 100000, and preferred upper limit is 700000.If the weight average molecular weight of said lactide (D, L, DL type)-epsilon-caprolactone copolymer etc. is lower than 100000, then can not obtain to bear the required intensity of arterial pressure sometimes.If surpass 700000, then the dissolubility in solvent reduces or the processability reduction sometimes.Be limited to 150000 under the weight average molecular weight of said lactide (D, L, DL type)-epsilon-caprolactone copolymer etc. preferred, be limited to 500000 on preferred.
As said porous layer, can enumerate non-woven fabrics, sponge or their complex etc.Wherein preferred non-woven fabrics.
Said porous layer is under the situation of non-woven fabrics, and the not special restriction of its weight per unit area is limited to 35g/m under preferred 2, be limited to 300g/m on preferred 2If the weight per unit area of said porous layer is less than 35g/m 2Even then the sowing cell perhaps makes cell invade sometimes, cell density can not uprise yet and make the regeneration of blood vessel be difficult to carry out, if surpass 300g/m 2, then cell is difficult to invade to porous layer inside and the regeneration of line artery sometimes.Be limited to 50g/m under the weight per unit area of said porous layer preferred 2, be limited to 250g/m on preferred 2
Said porous layer is under the situation of complex of sponge or sponge and non-woven fabrics, its aperture, density also with the situation of said non-woven fabrics under same.
The not special restriction of said porous layer thickness preferably is limited to 80 μ m down, is limited to 5mm on preferably.If said porous layer thickness less than 80 μ m, then can not be given full play to the effect as the support of revascularization sometimes.If surpass 5mm, then can not fully be close to blood vessel sometimes and fix.Be limited to 100 μ m under said porous layer thickness preferred, be limited to 4mm on preferred.
Said porous layer is under the situation of non-woven fabrics, can carry out hydrophilicity-imparting treatment.Through carrying out hydrophilicity-imparting treatment, can make it when contacting, promptly absorb this cell suspending liquid with cell suspending liquid, thereby can be more effectively and sow cell equably, in addition, can make cell more easily from around blood vessel invade.
The not special restriction of said hydrophilicity-imparting treatment for example can be enumerated: Cement Composite Treated by Plasma, glow discharge processing, Corona discharge Treatment, ozonization, surface grafting processing or ultraviolet radiation processing etc.Wherein, Cement Composite Treated by Plasma can improve water absorption rate significantly under the situation of the outward appearance that does not change non-woven fabrics, and is therefore preferred.
For the size of adjustment hole or density or improve the adhesiveness of cell, can said non-woven fabrics is integrated with the sponge that natural polymers such as protein such as polysaccharide, gelatin, collagen, albumin, fibrin such as, pectic acid plain by said biological absorptive material, starch, alginic acid, hyaluronic acid, shell and derivant thereof constitute.Through using this spongy layer and the integrated composite porous layer that obtains of non-woven fabrics of making, can realize good especially cell invasive.
Use 2cm * 10cm test film, be preferably below the 10cm as the method for benchmark stiffness that measure, prosthetic material for living organ of the present invention through the cantilever test method(s) stipulated in the stiffness A method with JIS L-1096.If said stiffness surpasses 10cm, then flexibility is insufficient and can not be close to blood vessel sometimes.
The not special restriction of the manufacturing approach of prosthetic material for living organ of the present invention; For example can enumerate following method etc.: after preparing said thin layer and porous layer respectively; With a part and the overlapping porous layer on the surface of organic solvent dissolution gained thin film, carry out drying and make it integrated.
The not special restriction of the method for preparing of said thin layer, for example can enumerate following method etc.: will in appropriate solvent, dissolve said biological absorptive material and the solution casting that obtains to release sheet, make its drying then.
The not special restriction of the method for preparing of said porous layer (non-woven fabrics); For example can enumerate following method etc.: needle point method; Utilize melt spinning method etc. to make the fiber of said biological absorptive material, make this fiber of braiding and the cloth that obtains is intertwined fibre machinery property through the needing machine that many pins are housed; Meltblown, from many nozzles simultaneously spray fused said biological absorptive material and make fine fibre on one side, make this fiber be spider reticulation on one side and dispose and make the uniform net of thickness, and make between the silk nature or mechanicalness gluing along all directions; The ESD method, through fused said biological absorptive material applied high voltage cause spray makes fine fibre on one side, on substrate, make even on one side and have the net of nano-scale fiber diameter, and make between the silk nature or mechanicalness gluing.
Prosthetic material for living organ of the present invention; At hypoplastic left heart syndrome, aortic arch stenosis, in the cardiopathic treatments of baby's congenital such as disconnected disease, make the insufficient repair materials that remedies the blood vessel area in its expansion particularly useful as on the aorta of narrow positions, cutting otch.In addition, can also be applicable to the treatment of Arteriosclerosis obliterans, true property aortic aneurysm (dissecting aneurysm), dissection of aorta etc.
In prosthetic material for living organ of the present invention, transplant the back cell from around blood vessel wriggle out and invade in the said porous layer.In addition, be present in vascular endothelial precursor cell in the blood circulation etc. and stick in the said porous layer, can also expect its migration or differentiation.Said porous layer becomes the support of revascularization, therefore, can early regenerate from the blood vessel of body by the utmost point.
Prosthetic material for living organ of the present invention not only goes for blood vessel, and goes for bladder (preventing spilling of body fluid), trachea (preventing spilling of air), intestinal tube and cartilage etc.
The prosthetic material for living organ of the present invention medicine that can in said porous layer, infiltrate uses.
The not special restriction of said medicine for example can be enumerated: as the aFGF of somatomedin, bFGF, EGF, VEGF, TGF-β, HGF etc.; As aspirin of antithrombotic agents etc.; As the heparin of anticoagulant, warfarin etc.; As the cilostazol of anti-platelet aggregation agent, aspirin etc.; As the andrographolide of glucocorticoid (steroid hormone), dexamethasone, hydrocortisone etc.; As the aspirin of nonsteroidal antiinflammatory drug (NSAID), diclofenac, indomethacin, ibuprofen, naproxen etc.
In addition; In order further to promote the regeneration of blood vessel; Can be before transplanting in said porous layer, sow endotheliocyte, medullary cell, smooth muscle cell or fibroblast with the mode that exsomatizes, after planting do not cultivate and directly transplant, or cultivate with the mode that exsomatizes after transplant.Perhaps, can not sow cell and directly use with stripped mode yet.
In addition, in the porous layer of prosthetic material for living organ of the present invention with the mode that exsomatizes sow cell, the transplanting of cultivating with the mode that exsomatizes again is with the manufacturing approach of prosthetic material for living organ, also belongs to one of the present invention.
In addition, thus through in the porous layer of prosthetic material for living organ of the present invention, sowing cell, cultivate with the regenerate cardiovascular system tissue method of reproduction of cardiovascular system tissue of the mode that exsomatizes again, also belong to one of the present invention with the mode that exsomatizes.
In addition; Through in the porous layer of prosthetic material for living organ of the present invention, sowing endotheliocyte, medullary cell, smooth muscle cell or fibroblast, cultivate the transplanting that obtains with the mode that exsomatizes again and use prosthetic material for living organ, also belong to one of the present invention with the mode that exsomatizes.
The invention effect
According to the present invention, can provide can be enough to bear arterial pressure and prevent spilling or the regenerated support of the vascular tissue of breaking, become blood of blood vessel and the prosthetic material for living organ that do not need to perform the operation once more etc. of blood.
Description of drawings
Fig. 1 is the photo of state of the blood vessel of the expression benefit of postoperative after 1,3,6 months part that prosthetic material for living organ of the present invention is arranged;
Fig. 2 is HE dyeing, ME dyeing and the painted microphotograph of VB (50 times on upper strata, 150 times of lower floors) of the blood vessel of the expression benefit of postoperative after 1 month part that prosthetic material for living organ of the present invention is arranged;
Fig. 3 is HE dyeing, ME dyeing and the painted microphotograph of VB (50 times on upper strata, 150 times of lower floors) of the blood vessel of the expression benefit of postoperative after 3 months part that prosthetic material for living organ of the present invention is arranged;
Fig. 4 is HE dyeing, ME dyeing and the painted microphotograph of VB (50 times on upper strata, 150 times of lower floors) of the blood vessel of the expression benefit of postoperative after 6 months part that prosthetic material for living organ of the present invention is arranged;
Fig. 5 is the painted microphotograph of α SMA (200 times) of the blood vessel of the expression benefit of postoperative after 1,3,6 months part that prosthetic material for living organ of the present invention is arranged;
Fig. 6 is the photo of state of the blood vessel of the expression benefit of postoperative after 12 months part that commercially available artificial blood vessel is arranged.
The specific embodiment
Below, enumerate embodiment and illustrate in greater detail embodiment of the present invention, still, the invention is not restricted to these embodiment.
(embodiment 1)
Utilize melt spinning method to make the fiber of L-lactide-epsilon-coprolactone copolymers (mol ratio 75: 25, weight average molecular weight 300000), make the cloth that weaves this fiber and obtain through the needing machine of many pins being housed, the preparation non-woven fabrics.The thickness of gained non-woven fabrics is about 3mm.
On the other hand, L-lactide-epsilon-coprolactone copolymers (mol ratio 50: 50, weight average molecular weight 200000) is dissolved in dioxane, prepares the dioxane solution of 4 weight %.Pour gained solution into glass dish, carry out air-dry and heat treatment, obtain the thin film that thickness is about 100 μ m thus.
Through a small amount of coating dioxane on the surface of a face of gained thin film this surface portion ground is dissolved, the non-woven fabrics that obtains of lamination above that, and carry out drying, and make thin film and non-woven fabrics integrated, obtain prosthetic material for living organ.The thickness of the prosthetic material for living organ that obtains in addition, is about 3mm.
(embodiment 2)
Utilize melt spinning method to make the fiber (35 Denier) that gathers Acetic acid, hydroxy-, bimol. cyclic ester, make the cloth that weaves this fiber and obtain through the needing machine of many pins being housed, the preparation non-woven fabrics.The thickness of gained non-woven fabrics is about 700 μ m.
On the other hand, L-lactide-epsilon-coprolactone copolymers (mol ratio 50: 50, weight average molecular weight 200000) is dissolved in dioxane, prepares the dioxane solution of 4 weight %.
Clamp the non-woven fabrics that obtains with glass plate, pour the solution of gained betwixt into after, under-40 ℃, freeze.Then ,-40～40 ℃ of following lyophilizing, heat treatment 12 hours, preparation non-woven fabrics and the incorporate material of sponge.The thickness of the non-woven fabrics-sponge that obtains is about 1mm.
L-lactide-epsilon-coprolactone copolymers (mol ratio 50: 50, weight average molecular weight 200000) is dissolved in dioxane, prepares the dioxane solution of 4 weight %.Pour gained solution into glass dish, carry out air-dry and heat treatment, obtain the thin film that thickness is about 100 μ m thus.
Through a small amount of coating dioxane on the surface of a face of gained thin film this surface portion ground is dissolved, non-woven fabrics-sponge of obtaining of lamination above that, and carry out drying, and make thin film and non-woven fabrics-sponge integrated, obtain prosthetic material for living organ.The thickness of the prosthetic material for living organ that obtains in addition, is about 1mm.
(zoopery evaluation)
The descending aorta of Canis familiaris L. (beagle, body weight are about 10kg) is longitudinally cut 30mm, fill among the embodiment 1 prosthetic material for living organ made (20mm * 30mm), and use Pu Liling (Prolene) suturing with thread management of diameter 6-0 to fix around herein.Postoperative has the part of prosthetic material for living organ not observe breaking of spilling of blood or blood vessel fully from benefit.
Postoperative 1,3 and implement euthanasia after 6 months takes out the blood vessel of mending the part that prosthetic material for living organ is arranged.Fig. 1 representes benefit is had the photo of the state that the blood vessel of the part of prosthetic material for living organ longitudinally cuts.In addition, make tissue slice, hematoxylin-eosin (HE) dyeing, horse gloomy trichroism (MS) dyeing and the painted microphotograph of Victoria blue (VB) near Fig. 2～4 expression suturing parts, Fig. 5 representes the painted microphotograph of α smooth muscle actin (α SMA).
Can be found out that by Fig. 1 although there is individual variation, postoperative is mended the intravascular space face endothelialization of the part of prosthetic material for living organ in the time of 1 month, its general survey 3 months after surgery, 6 months is ripe more, has formed more near the tissue from the body arterial wall.
In Fig. 2～5, the image upside is that blood vessel is inboard, and from postoperative beginning in 1 month, can observe with the blood vessel inboard is the propagation of the tissue at center, but few in the intrusion of the inner cell of non-woven fabrics.Arrive postoperative in the time of 3 months, internal film tissue's thickening that blood vessel is inboard, and the thickness attenuation of non-woven fabrics on the other hand.Postoperative is in the time of 6 months, decomposes basically, absorbs as the non-woven fabrics of support, and be the extracellular matrix propagation at center with VSMC and collagen fiber, formed more sophisticated blood vessel wall structure.
(reference example)
On the aorta of the descending aorta portion of Canis familiaris L. (beagle, body weight are about 10kg), longitudinally cut the otch of 30mm and make its expansion.For the deficiency of the area that remedies this blood vessel, fill the commercially available artificial blood vessel (trade name Gelseal is coating gelatin and the material that obtains on fluororesin) of 20mm * 30mm, and fix with suture around.Postoperative has the part of artificial blood vessel not manage in benefit and observes spilling of blood or breaking of blood vessel.
Postoperative is implemented euthanasia after 12 months, take out the blood vessel of mending the part that artificial blood vessel is arranged.Fig. 6 representes benefit is had the photo of the state that the blood vessel of the part of artificial blood vessel longitudinally cuts.
Can judge that by Fig. 6 although postoperative has reached 12 months, endothelialization does not almost make progress.
Utilize probability on the industry
According to the present invention, can provide can be enough to bear arterial pressure and prevent spilling or the regenerated support of the vascular tissue of breaking, become blood of blood vessel and the prosthetic material for living organ that do not need to perform the operation once more etc. of blood.

Claims (8)

1. prosthetic material for living organ is made up of the layered product of thin layer and porous layer, and said thin layer is made up of biological absorptive material; Said porous layer is made up of biological absorptive material; Said prosthetic material for living organ can be enough to bear arterial pressure and prevent spilling of blood or breaking of blood vessel, becomes the regenerated support of vascular tissue, and does not need to perform the operation once more; It is characterized in that
Said thin layer is that the lactide-epsilon-coprolactone copolymers of 40 moles of %～80 mole % constitutes by the content of lactide, and said lactide comprises D type, L type and DL type,
Said porous layer is made up of non-woven fabrics, and said non-woven fabrics is that the lactide-epsilon-coprolactone copolymers of 40 moles of %～80 mole % constitutes by the content of lactide, and said lactide comprises D type, L type and DL type.
2. prosthetic material for living organ as claimed in claim 1 is characterized in that, the thickness of thin layer is the scope of 30 μ m～1mm.
3. prosthetic material for living organ as claimed in claim 1 is characterized in that, the weight per unit area of nonwoven layer is 35～300g/m 2Scope.
4. prosthetic material for living organ as claimed in claim 1 is characterized in that, the stiffness of use the test film of 2cm * 10cm, measuring through the cantilever test method(s) stipulated in the stiffness A method with JIS L-1096 as the method for benchmark is as below the 10cm.
5. prosthetic material for living organ as claimed in claim 1 is characterized in that, infiltration has medicine in the porous layer.
6. prosthetic material for living organ as claimed in claim 1 is characterized in that, has sowed cell with the mode that exsomatizes in the porous layer.
7. prosthetic material for living organ as claimed in claim 6 is characterized in that, the cell of sowing is a medullary cell.
8. prosthetic material for living organ is made up of the layered product of thin layer and porous layer, and said thin layer is made up of biological absorptive material; Said porous layer is made up of biological absorptive material; Said prosthetic material for living organ can be enough to bear arterial pressure and prevent spilling of blood or breaking of blood vessel, becomes the regenerated support of vascular tissue, and does not need to perform the operation once more; It is characterized in that
Said thin layer is that the lactide-epsilon-coprolactone copolymers of 40 moles of %～80 mole % constitutes by the content of lactide, and said lactide comprises D type, L type and DL type,
Said porous layer is made up of the complex of sponge and non-woven fabrics; Said sponge is that the lactide-epsilon-coprolactone copolymers of 40 moles of %～80 mole % constitutes by the content of lactide; Said lactide comprises D type, L type and DL type, and said non-woven fabrics constitutes by gathering Acetic acid, hydroxy-, bimol. cyclic ester.
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EP2174619A4 (en) 2012-11-28
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